It is assumed that there are 518 human kinase genes. Kinases are enzymes that catalyze substrate-specific phosphorylation. The kinases change phosphorylation states of substrates while acting complementarily to phosphatases, which perform the reversal reaction, i.e., dephosphorylation. Thus, activation states of the substrates are controlled. Networks constituted by kinases form various signaling mechanisms in organism. Kinases play roles as switches for signal transduction. In a typical case, the signal transduction is initiated by binding of a growth factor or the like to a Receptor Tyrosine Kinase (RTK) on cell membrane to cause autophosphorylation of the RTK. Then, a protein located downstream of the RTK is phosphorylated and, as a result, various cellular responses, namely, metabolism, transcription, proliferation, cell migration, apoptosis, or cell differentiation, are caused.
Recently, an approach to identify molecules that are involved in abnormal physiological phenomena characteristically observed in cancer cells and to utilize these molecules as targets, namely, drugs based on a concept called molecular targeting have been attracting an attention of the researchers (Non-Patent Document 1). The molecular targeting reagents are actively being studied in expectation of a significant decrease in serious side effects that cannot be avoided by existing anticancer agents and expectation of significant effects on refractory cancers, advanced cancers, and metastatic cancers. Kinases are typical molecular targets. Networks formed in cells by a group of kinases, regulatory factors thereof, related proteins, and so on are highly complexed, and, as matters stand, clarification of the entire picture of their functions requires further investigation. However, relation between abnormalities in the networks and diseases such as cancer is gradually being clarified. Consequently, kinases have increasingly come to occupy a central position as targets of molecular targeting drugs (Non-Patent Document 2). Many types of kinases are investigated for the use as molecular targets. Actually, drugs and antibodies targeting on ErbB1 (EGFR/HER1) or ErbB2 (HER2), which belongs to RTK group, and drugs targeting on Bcr/Abl, which is one of non-RTK, have been already put into practice and clinically used. Other kinases, for example, kinases involved in a Ras signal transduction pathway, kinases involved in angiogenesis, and Flt3 kinases, also can serve as molecular targets. Typical examples will be described below.
The Ras signal transduction pathway plays an important role in controlling cell proliferation, differentiation, and transformation. The activation of Ras protein is initiated by the action of an extracellular signal such as a growth factor to a receptor on a cell surface. The activated Ras protein interacts with Raf, one of serine/threonine protein kinases, to activate the Raf (Non-Patent Documents 3 and 4). It is known that there exist three isoforms of Raf protein, namely A-Raf, B-Raf, and Raf-1 (c-Raf). These isoforms are different from each other in interaction with Ras protein, ability for activating a substrate MEK, and expression distribution in organs. A study using knockout mice shows that B-Raf and Raf-1 are essential for survival. The activated Raf activates MEK, and subsequently the activated MEK activates ERK (MAPK). The ERK finally activates various substrates, such as transcription factors, in cytoplasm or in a cell nucleus to cause cellular changes (proliferation, differentiation, and transformation) corresponding to extracellular signals. These cellular changes such as proliferation are suitably controlled in normal cells. However, it is observed that about 20% of Ras proteins are always in an activated state (GTP complex) in human cancer cells. As a result of this mutation, a proliferation signal to a Raf/MEK/ERK cascade is maintained. Thus, Raf is known to play an important role in proliferation of human cancer cells (Non-Patent Document 5). Furthermore, in a recent study, it is reported that 66% of melanoma cells, 15% of colon cancer, and 14% of liver cancer have mutations in B-Raf to keep Raf/MEK/ERK cascade activated (Non-Patent Document 6). In addition to the role as a direct downstream effector of the Ras protein in the Raf/MEK/ERK cascade described above, it is known that the Raf kinase plays a central role for inhibiting cell apoptosis in various mechanisms (Non-Patent Documents 7 and 8).
According to the above, blockage of Ras signaling by Raf kinase inhibition, which plays an important role in cancer cell proliferation is suggested to be useful for cancer therapy. Actually, it is reported that the growth of various types of human cancer is suppressed in vitro and in vivo by inhibiting the expression of Raf using an antisense RNA (Non-Patent Document 9).
On the other hand, angiogenesis is an indispensable process for the growth of solid cancers. Cancer cells absorb necessary oxygen and nutrients from surroundings. As a result of the growth of solid cancer, low oxygen pressure, poor nutrition, and low pH, namely, hypoxia, occur in a region more than 1 to 2 mm apart from the nearest blood vessel. The cancer cells response against this stress by producing various angiogenesis factors to stimulate angiogenesis from vascular endothelial cells present in the vicinity. Consequently, the solid cancer can further grow. The angiogenesis consists of three steps: 1) disruption of vascular wall basement membrane, 2) migration and proliferation of vascular endothelial membrane, and 3) tube formation. In each step, such growth factors as b-FGF (basic fibroblast growth factor), PDGF (platelet-derived growth factor), and VEGF (vascular endothelial growth factor) are working. In particular, VEGF, which is a vascular endothelial cell-specific growth factor, is essential in all the above three steps and is thought to play a central role in angiogenesis. It has been known that VEGF binds to three types of receptor tyrosine kinases, VEGFR-1 (flt-1), VEGFR-2 (flk-1, KDR), and VEGFR-3 (flt-4). KDR performs autophosphorylation that highly depends on the ligand and is thereby thought to be indispensable for VEGF-dependent biological response. On the basis of the above-described reasons, recently, angiogenesis inhibitors targeting VEGF or or inhibiting tyrosine kinase activity of VEGFR such as KDR have been actively developed as molecular targeting drugs (Non-Patent Documents 10 and 11). In addition to VEGF, growth factor receptors relating to angiogenesis, such as FGFR, PDGFR, TIE-2, and c-Met, are suggested to be directly or indirectly involved in angiogenesis. Kinase inhibitors against these receptors are being investigated as therapeutic agents for angiogenic diseases such as cancer (Non-Patent Document 12). Furthermore, the above-described Raf kinase is known to have an indirect relation to angiogenesis. That is, b-FGF activates Raf-1 by phosphorylating serines at positions 338 and 339 through PAK-1 (p21-activated protein kinase-1) to inhibit apoptosis, independent from MEK1. On the other hand, a VEGF signal activates Raf-1 by phosphorylating tyrosines at positions 340 and 341 through Src kinase to protect endothelial cells from apoptosis, dependent on MEK1. Thus, it is clear that Raf plays roles not only in proliferation of cancer cells but also in control of endothelial cell survival in angiogenesis (Non-Patent Document 13). Angiogenesis is a physiological phenomenon indispensable for intrauterine embryogenesis, wound healing in adults, a menstrual cycle of adult females, and so on. It is reported that abnormal angiogenesis in an adult individual is involved in diseases such as psoriasis, atherosclerosis, chronic rheumatoid arthritis, endometriosis, diabetic retinopathy, and age-related macular degeneration (Non-Patent Documents 14, 15, and 16). Molecular targeting drugs targeting to angiogenesis is expected to be useful for not only cancer therapy but also therapy of these diseases accompanied by angiogenic abnormalities.
FMS-like tyrosine kinase 3 (FLT3) is an RTK belonging to the same family as that of PDGFR and is expressed in undifferentiated hematopoietic cells to transmit signals for proliferation and survival of hematopoietic cells by binding to a ligand FL that is expressed in the bone marrow and other organs. A mutation of FLT3 is observed in about 30% of acute myeloid leukemia (AML) and about 5% of myeloid dysphasia syndrome (MDS). The type of the mutation is internal tandem duplication (ITD) in a juxtamembrane domain right below transmembrane region or point mutation in activation loop (D835) in a kinase region (Non-Patent Document 17). The variation causes ligand-independent activation to transport signals for abnormal proliferation and anti-apoptosis, and is thought to be highly involved in progress of, in particular, acute myeloid leukemia (AML).
Recently, drugs called a multikinase inhibitor or a broad-specific inhibitor, which are expected to exhibit high therapeutic effects by inhibiting some targets together, not selectively inhibiting only one kinase as a molecular target, have been developed (Non-Patent Documents 18 and 19). There are still many questions in medicinal chemistry methodology to identify a specific kinase group that can be a target of a multikinase inhibitor for achieving an excellent therapy effect and suppressing side effects, and further investigation is highly desired. However, multikinase inhibitors are expected as an effective means of overcoming the above problems when heterogenecity of cancer cells and formation of drug resistance are taken into consideration and, therefore, are widely studied. For example, the following compound BAY 43-9006 (the compound disclosed in Example 41 of Patent Document 1) has been reported.

The above compound is a Raf-1 and B-RAF inhibitor and is reported as an inhibitor of kinases involved in angiogenesis and cancer progress, such as KDR, VEGFR-3, Flt-3, c-KIT, and PDGFR-β (Non-Patent Document 20). However, the results of the phase 1 clinical trial of this compound (Non-Patent Document 21) indicate the problems that the compound is rather lipophilic and poorly water soluble, the interpatient variability of pharmacokinetics parameters is observed, and the compound tends to be accumulated by frequent administration. These problems are thought to be caused by the low solubility to water due to the high hydrophobic property and high crystal property due to a phenylurea skeleton. The low solubility to water is a serious problem, particularly, in clinical development of oral drugs. That is, this property easily leads to the problems of a decrease in absorption, unstable effects because of interpatient variability in pharmacokinetics, and the accumulation tendency (Non-Patent Documents 22 and 23).
Many urea compounds that exhibit anticancer effects by inhibiting either Raf or any kinase (for example, KDR or PDGFR) involved in angiogenesis have been reported (Patent Documents 2 to 13). For example, International Publication No. WO 02/32872 (Patent Document 2) discloses a compound having an angiogenesis inhibitory activity due to inhibition of KDR, but does not disclose a Raf-1 inhibitory activity.
[Patent Document 1] International Publication No. WO 00/42012
[Patent Document 2] International Publication No. WO 02/32872
[Patent Document 3] International Publication No. WO 98/52559
[Patent Document 4] International Publication No. WO 99/32106
[Patent Document 5] International Publication No. WO 99/32436
[Patent Document 6] International Publication No. WO 99/32455
[Patent Document 7] International Publication No. WO 02/62763
[Patent Document 8] International Publication No. WO 02/85857
[Patent Document 9] International Publication No. WO 03/47579
[Patent Document 10] International Publication No. WO 03/68223
[Patent Document 11] International Publication No. WO 03/40228
[Patent Document 12] International Publication No. WO 03/40229
[Patent Document 13] International Publication No. WO 03/68746
[Non-Patent Document 1] Igaku no Ayumi (Journal of Clinical and Experimental Medicine) 2000, 194, 817-823.
[Non-Patent Document 2] Science 2002, 298, 1912-1934.
[Non-Patent Document 3] Trends Biochem. Sci. 1994, 19, 474-480.
[Non-Patent Document 4] Science 1994, 264, 1463-1467.
[Non-Patent Document 5] Annual Reports in Medicinal Chemistry 1994, 29, 165-174.
[Non-Patent Document 6] Nature 2002, 417, 949.
[Non-Patent Document 7] Biochemical Pharmacology 2003, 66, 1341-1345.
[Non-Patent Document 8] Science 2004, 306, 2267-2270.
[Non-Patent Document 9] Nature 1991, 349, 426-428.
[Non-Patent Document 10] J. Clinical Oncology 2003, 21, 60-65.
[Non-Patent Document 11] Expert Opinion Investigational Drugs 2003, 12, 51-64.
[Non-Patent Document 12] J. Cell Biol. 1995, 129, 895-898.
[Non-Patent Document 13] Science 2003, 301, 94-96.
[Non-Patent Document 14] New England Journal of Medicine 1995, 333(26), 1757-1763.
[Non-Patent Document 15] Angiogenesis 2002, 5(4), 237-256.
[Non-Patent Document 16] J. Clinical Endocrinology and Metabolism 2004, 89(3), 1089-1095.
[Non-Patent Document 17] Leuk Lymphoma 2002, 43, 1541-1547.
[Non-Patent Document 18] Nature Biotechnology 2005, 23(6), 237-256.
[Non-Patent Document 19] New Current 2004, 15(22), 2-13.
[Non-Patent Document 20] AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Proceedings 2003, page 69, A78.
[Non-Patent Document 21] American Society of Clinical Oncology Annual Meeting (May 18 to 21, 2002), 2002 Abstract Nos. 121, 1816, and 1916.
[Non-Patent Document 22] Pharmazeutische Industrie 2002, 64(8), 800-807.
[Non-Patent Document 23] Pharmazeutische Industrie 2002, 64(9), 985-991.